Neuromodulatory effects of pudendal nerve stimulation on bladder hypersensitivity are present in opioid-pretreated rats

Background and objectives: Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models and anecdotally reduces pain in humans with pelvic pain of urologic origin. Concomitant opioids are known to alter responses to neuromodulation in some systems. So prior to the development of a clinical trial for purposes of regulatory approval, the preclinical interaction between opioids and stimulation effectiveness was examined.

Methods: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Morphine was administered acutely (1-4 mg/kg intraperitoneal) or chronically (5 mg/kg subcutaneously daily for 2 weeks prior to the terminal experiment). bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMR; abdominal muscle contractile responses to urinary bladder distension (UBD)) were used as nociceptive endpoints.

Results: Morphine produced a dose-dependent inhibition of VMRs to UBD that was naloxone reversible. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received acute or chronic subcutaneous morphine injections.

Conclusions: This study suggests that inhibitory effects of bPNS can still be evoked in subjects who are receiving opioid therapy, thus giving guidance to potential clinical trials seeking regulatory approval for the treatment of chronic bladder pain.